Endothelium-derived C-type natriuretic peptide offsets the pathogenesis of pulmonary hypertension

Abstract

In the systemic circulation, C-type natriuretic peptide (CNP) fulfils a multimodal homeostatic function, modulating many processes relevant to pulmonary hypertension (PH), including local blood flow, vascular remodeling and cardiac function. We explored a parallel, protective role for CNP in the pulmonary circulation and right ventricle, and investigated the potential for exploiting natriuretic peptide receptor (NPR) signaling in the context of PH. The development of PH was explored in wildtype (WT), endothelium-restricted (ecCNP-/-), and cardiomyocyte-specific (cmCNP-/-) CNP knockout mice, and global NPR-C (NPR-C-/-) animals exposed to hypoxia (10 % O2) plus the vascular endothelial growth factor receptor antagonist Sugen (SuHx) for 5 weeks. To investigate the therapeutic potential of NPR signaling, exogenous CNP was administered via subcutaneous osmotic minipump to animals with established PH. The development of PH, including right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH) and RV fibrosis, was accentuated in ecCNP-/- mice exposed to SuHx, whereas global deletion of NPR-C specifically exacerbated the development of RVH and fibrosis without altering RVSP. In contrast, loss of cardiomyocyte-derived CNP did not result in a significant adverse phenotype. Pharmacological CNP administration significantly reduced RVSP and promoted anti-proliferative, anti-remodeling signaling in the cardiopulmonary circulation. These data elucidate the protective role of endogenous CNP signaling against the development of PH and provide preliminary evidence for the therapeutic potential of targeting CNP-dependent pathways, including both cognate NPR-B and NPR-C, in the context of pulmonary vascular disease and RV remodeling.

Keywords

• Natriuretic peptide
• Natriuretic peptide receptor
• Pulmonary hypertension
• Vascular remodeling
• Right ventricular fibrosis